ClinVar Miner

Submissions for variant NM_001351834.2(ATM):c.1562_1563GA[1] (p.Glu522fs) (rs587779817)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000211964 SCV000149053 pathogenic not provided 2018-07-25 criteria provided, single submitter clinical testing The ATM c.1564_1565delGA deletion causes a frameshift, which changes a Glutamic Acid to an Isoleucine at codon 522, and creates a premature stop codon at position 43 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. ATM c.1564_1565delGA, also reported as c.1563_1564delAG and c.1561_1562delAG, has been observed in individuals with recessively inherited Ataxia-telangiectasia and in patients with breast cancer, gastric cancer, and an unspecified Lynch syndrome-related cancer and/or polyps (Byrd 1996, Demuth 2011, Verhagen 2012, Driessen 2013, Huang 2015, Hansford 2015, Yurgelun 2015, Mansfield 2016). We consider this variant to be pathogenic.
Ambry Genetics RCV000115144 SCV000185620 pathogenic Hereditary cancer-predisposing syndrome 2018-10-13 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000169147 SCV000219160 pathogenic Ataxia-telangiectasia syndrome 2019-12-24 criteria provided, single submitter clinical testing This sequence change deletes 2 nucleotides from exon 10 of the ATM mRNA (c.1564_1565delGA), causing a frameshift at codon 522. This creates a premature translational stop signal (p.Glu522Ilefs*43) and is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs751357509, ExAC 0.009%). This variant has been observed in individuals affected with ataxia-telangiectasia (PMID: 9463314, 10817650, 9000145, 12497634, 21965147, 10330348), including five homozygous individuals (PMID: 10817650, 10330348), and an individual with breast cancer (PMID: 27083775). This variant is also known as 1561delAG, 521 AG, 1563_1564delAG, 1563delAG, c.1564_1565delAG and c.1561_1562delAG in the literature. ClinVar contains an entry for this variant (Variation ID: 127340). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000169147 SCV000220368 pathogenic Ataxia-telangiectasia syndrome 2014-06-03 criteria provided, single submitter literature only
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000211964 SCV000610563 pathogenic not provided 2017-08-29 criteria provided, single submitter clinical testing
Color RCV000115144 SCV000681982 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115144 SCV000821698 pathogenic Hereditary cancer-predisposing syndrome 2020-01-01 criteria provided, single submitter clinical testing This variation is a deletion of 2 nucleotides in exon 10 of the ATM mRNA (c.1564_1565delGA), causing a frameshift after codon 522 and the creation of a premature translational stop signal 43 amino acid residues later -p.(Glu522Ilefs*43). This is expected to result in an absent or disrupted protein product. Truncating variants in ATM are known to be pathogenic. This particular variant has been reported in the literature in individuals affected with ataxia-telangiectasia and in breast cancer patients (PMID: 10817650, PMID: 12497634, PMID: 27083775). The mutation database ClinVar contains multiple entries for this variant (Variation ID: 127340).
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000709705 SCV000839878 pathogenic Familial cancer of breast 2017-01-30 criteria provided, single submitter clinical testing This c.1564_1565del (p.Glu522Ilefs*43) has previously been reported a patient with ataxia telangiectasia [p.R521fs in PMID 8789452]. It has also been reported in patients with gastric cancer and suspected lynch syndrome [c.1561_1562del, p.R521fs in PMID 26506520]. This c.1564_1565del (p.Glu522Ilefs*43) variant been observed in 6 heterozygous individuals in the ExAC population database (http://exac.broadinstitute.org/variant/11-108121752-CAG-C). It is thus interpreted as a likely pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000169147 SCV000918549 pathogenic Ataxia-telangiectasia syndrome 2018-07-09 criteria provided, single submitter clinical testing Variant summary: ATM c.1564_1565delGA (p.Glu522IlefsX43) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 5.3e-05 in 246034 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (5.3e-05 vs 0.004), allowing no conclusion about variant significance. The variant, c.1564_1565delGA, has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (Demuth_2011, Stankovic_1998, Sandoval_199). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submission from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Athena Diagnostics Inc RCV000211964 SCV001143097 pathogenic not provided 2019-07-05 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.
Institute of Human Genetics,Klinikum rechts der Isar RCV000169147 SCV001150019 pathogenic Ataxia-telangiectasia syndrome 2019-02-21 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000211964 SCV001249798 pathogenic not provided 2019-09-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197862 SCV001368645 pathogenic Hyperactivity; Delayed speech and language development; Joint hypermobility; Intellectual disability, moderate; Muscular hypotonia 2019-08-20 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2. This variant was detected in heterozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198976 SCV001369971 pathogenic Dystonia; Scoliosis; Delayed speech and language development; External ophthalmoplegia; Tremor; Noncommunicating hydrocephalus; Mild global developmental delay 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM2,PP2,PP3. This variant was detected in heterozygous state.
Institute of Human Genetics, University of Leipzig Medical Center RCV000709705 SCV001428899 pathogenic Familial cancer of breast 2018-04-12 criteria provided, single submitter clinical testing
GeneReviews RCV000169147 SCV000328297 pathogenic Ataxia-telangiectasia syndrome 2016-10-27 no assertion criteria provided literature only

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